In 1999 we reported an important demonstration of a working brain-machine interface (BMI), in which recordings from multiple, single neurons in sensorimotor cortical areas of rats were used to directly control an arm to retrieve a water reward (Chapin, Moxon et al., 1999). Recent studies in humans with spinal cord injury have shown that recording from multiple, single neurons can be used by the patient to control the cursor on a computer screen. The promise is that one day it will be possible to use these control signals from neurons to re-activate the patient's own limbs. However, the ability to record from large populations of single neurons for long periods of time has been hampered because either the electrode itself fails or the immunological response of the tissue surrounding the microelectrode produces a glial scar, preventing single-neuron recording. While appropriate insulating materials have largely solved the problem of electrode failure, much less is known about the immunological response to insertion of a microelectrode, its effect on neuronal recordings and, of greatest importance, how it can be reduced. The long-term goal of our work is to develop a bioactive, multisite, single neuron recording electrode that can record at least one single neuron from 100% of the recording sites for more than one year in rat and ten years in primates. The objective of this proposal is to identify intervention strategies that, when combined, will allow high quality, single neuron recordings for one year in the rat. It is our central hypothesis that because the development of a glial scar is due to two separate mechanisms: mechanical damage to neurons due to electrode insertion and sustained immunological response to the foreign body (i.e., the microelectrode), multiple interventions are necessary to ensure long-term recordings of single neurons. The rationale for this proposal is that if both of these mechanisms that contribute to the glial scar are ameliorated, then it will be possible to record more single neurons, longer, with better signal-to-noise. We use immunohistochemistry and electrophysiology to assess the effect of different interventions on the formation of a glial scar and neuronal activity. We are well prepared to undertake this research because we have experience in 1) electrophysiological recordings for BMI, 2) electrode development, having developed a ceramic-based, multi-site microelectrode recording device (CBMSE array), with superior strength and insulating properties compared to silicon based microelectrodes, 3) immunohistochemical methods to study the effects of injury on neuronal tissue and 4) the study of the mechanisms of neural cell injury and the effects of repair agents on neuronal survival. There are three primary motivations for perfecting the ability to record single neurons for long periods of time from chronically implanted arrays of microelectrodes: 1) to better understand neuronal function, 2) to develop novel brain-machine interface devices and sensors and 3) for clinical applications in neurorobotics. While it has been demonstrated that chronically implanted microelectrodes can be used as the neural interface in a brain machine interface for the treatment of paralyzed and disabled patients, if the neural interface could be enhanced such that the neuronal recordings can be sustained for decades, then the maximum potential benefit can be realized. However, in the short term, even moderate improvements in the recording capabilities of microelectrodes will enhance our ability to understand how ensembles of neurons code for motor commands, the role of plasticity in these circuits and most importantly how these circuits in the brain are modified after disease or injury. [unreadable] [unreadable]